Statin Monotherapy for Treatment of Endocrine Metabolic Disease Risk

Rationale: Individuals with motor-complete spinal cord injury (SCI) undergo dramatic changes
in body composition in the first 18 months post-injury, including declines in bone mineral
density (BMD) that increase lower-extremity fragility fracture risk, and increases in fat
mass that increase cardio-metabolic disease (CMD) risk. While statins are an effective
treatment for dyslipidemia, research evidence suggests additional pleiotropic effects on bone
through promotion of osteogenesis, suppression of osteoblast apoptosis, and inhibition of
osteoclastogenesis. There are currently no effective therapies to treat sublesional
osteoporosis (SLOP) and reduce the risk of fragility fractures in individuals with SCI.

Hypothesis: Twelve months of statin therapy with concurrent coenzyme Q10 (CoQ10), to reduce
risk of statin neuromyotoxicity, and standard care (calcium 1250mg OD and vitamin D3 2000IU
OD) will be superior to placebo with CoQ10 and standard care, for augmenting knee region BMD
and reducing inflammatory stress (hs-CRP), thereby reducing endocrine metabolic disease risk.

Objective: To determine the safety and efficacy of statin therapy for augmenting distal
femoral BMD among adults with chronic motor-complete SCI in Toronto, Ontario and Miami,
Florida.

Study Design: Multi-centre, double-blind, randomized controlled Phase II safety and efficacy
trial.

Subjects: Consenting men and premenopausal women (N=54, age 18-60 yrs) with chronic (≥2
years) spinal cord injury with a neurological level between C1-T10 and an AIS category of
A/B.

Intervention: Rosuvastatin 10 mg po daily at night versus placebo for 12 months. All subjects
will receive osteoporosis standard care (calcium carbonate 1250mg po daily and vitamin D3
2000 IU po daily) to maintain bone mass and CoQ10 100mg po daily to prevent statin-induced
myopathy.

Outcomes: Primary safety outcomes: i) establish the safety of rosuvastatin in chronic SCI by
reporting the frequency of myotoxicity and type II diabetes onset; ii) frequency and mean
duration of liver transaminase elevations in the rosuvastatin and placebo groups. Primary
efficacy outcome: measure the mean between group absolute changes in distal femur areal BMD
(aBMD, g/cm2) from baseline to one year. Secondary efficacy outcomes: will examine the mean
absolute changes from baseline in: i) volumetric BMD (vBMD, g/cm3); ii) markers of bone
turnover - Bone Specific Alkaline Phosphatase (BALP), telopeptide (CTX), Sclerostin and RANK
Ligand (RANK-L); iii) serum inflammatory markers including high sensitivity C-reactive
Protein (hs-CRP), Interleukin-1ß (IL-1ß). interleukin-6 (IL-6), tumor necrosis factor - alpha
(TNF-alpha), erythrocyte sedimentation rate (ESR); and, iv) lipid profile; low density
lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), triglycerides, and
total cholesterol Clinical Implications: Should rosuvastatin prove to be safe and efficacious
for reducing endocrine metabolic disease risk for adults with chronic SCI, the results will
advance the health of people with SCI by reducing the frequency and severity of heart disease
and fracture as they age, with a single intervention.

Inclusion Criteria:

- Adult (age 18-60 years)

- Motor complete SCI (C1-T10 AIS A/B)

- 2 years post-injury

- Have a telephone, and ability to attend the study visits

- Able to take oral medications and swallow independently

- Can provide free and informed consent

- Ability to understand instructions in English

Exclusion Criteria:

These criteria are intended to exclude those in whom; Rosuvastatin would be unsafe,
DXA/pQCT measurement or biomarker assessment would be invalid, or in whom other co-morbid
health conditions may confound the study results. Exclusion criteria include:

- Current and/or one year prior to enrolment treatment with any statin such as
atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and
rosuvastatin.

- Current treatment with an oral or IV bisphosphonate, denosumab, recombinant PTH,
ovarian hormone therapy, an oral contraceptive, Immunosuppressants (Including
Cyclosporine) and fusidic acid.

- Known allergy to Rosuvastatin, lactose powder, CoQ10, calcium carbonate, vitamin D2
and vitamin D3, or any other ingredient found in rosuvastatin, placebo or study
supplements.

- History of Paget's disease, osteomalacia, steroid induced osteoporosis, or untreated
parathyroid or untreated thyroid disease.

- Subjects with history of stage 4 chronic kidney disease. (124)

- Current Weight ≥136 kg.

- Bilateral knee region metal implants (hardware), history of bilateral knee region
contracture >30 degrees, fracture or any other bilateral knee region pathology which
would preclude accurate DXA assessment of one limb.

- Post-menopausal women (absence of menses for a minimum of 1 year).

- Women with amenorrhea due to bilateral surgical removal of the ovaries and/or uterus
(women with amenorrhea due to spinal cord injury are able to participate).

- Pregnancy or lactation.

- Female of child-bearing potential who is engaged in active heterosexual relations and
is not using appropriate birth control methods. Appropriate methods of birth control
will include: surgical sterilization at least 6 months prior to using study drug or
sexual activity restricted to a vasectomized partner, barrier contraception with a
condom or diaphragm in conjunction with spermicidal gel in use at least 30 days prior
to using study drug OR sexual abstinence as a lifestyle.

- History of liver disease or abnormal Aspartate Aminotransferase (AST) or Alanine
Aminotransferase (ALT), ≥1.5 times the upper limit of the normal reference range at
enrolment.

- History of symptomatic hypocalcemia or hypophosphatemia.

- Concurrent treatment with prednisone (>7.5mg/day for 90 days).

- Vitamin D deficiency (Serum Vitamin D level <75nmol/L) after completing 8 to 12 weeks
of treatment for Vitamin D deficiency as per the Vitamin D correction protocol
(Appendix Page 1).

- History of heart attack or stroke.

- Untreated hypertension defined as: elevated BP above (135/85mmHg) assessed with an
automated blood pressure cuff at 3 distinct time points in a 7-10 day period.(125,
126)

- Current alcohol or street drug abuse.

- Any illness or condition interfering with the trial conduct or subject safety.